We previously described the radiosynthesis and preliminary biodistribution of 3-(3-(3-[F-18]fluoropropyl)thio)-1,2,5,thiadiazol-4-yl)-1,2,5,6-tetrahydr o-1-methylpyridine ([F-18]FP-TZTP, a muscarinic M2 selective ligand. In collaboration with NIMH investigators, we recently began studies in normal human volunteers, with the eventual goal of studying patients with Alzheimer's disease. The initial analysis, based on data from six young control subjects, concentrated on the determination of the appropriate kinetic model for [F-18]FP-TZTP in humans. In plasma, parent compound represented 68 plus or minus 8, 41 plus or minus 9, and 14 plus or minus 4 percent of radioactivity at 20, 40, and 120 min, respectively. The plasma free fraction (fp) was 5.9 plus or minus 1.2 percent. A model with one tissue compartment produced an excellent fit for the full 120 min of data, so that the additional parameters of a two-compartment model were unidentifiable. K1 values in gray matter regions were high?0.36 to 0.56 ml/min/ml?and showed excellent correlation with CBF. V values, representing total tissue binding, were very similar in cortical regions, basal ganglia, and thalamus, but were significantly higher (p less than .01) in amygdala. Unlike the results in the monkey, binding in the cerebellum was similar to that in the cerebral cortex. V values correlated with fp and normalization of V by fp reduced the coefficient of variation of V from 24 to 16 percent. The methodology and results from our analysis of [F-18]FP-TZTP data in young controls provide the basis for ongoing studies in elderly controls and patients with Alzheimer's disease. Another goal is to develop a series of F-18-labeled radiopharmaceuticals that are serotonin 5-HT-1A subtype specific and have a range of binding affinities. We evaluated [F 18]FCWAY in rhesus monkeys with PET. The goal of these studies was to further develop [F-18]FCWAY as a radioligand to measure 5-HT-1A receptors in humans. Studies included control experiments to develop an appropriate kinetic model and preblocking studies to demonstrate specific binding and estimate the level of nonspecific binding. Separate experiments with injection of the labeled metabolites of [F-18]FCWAY were also performed to determine if significant brain accumulation occurred. Control [F-18]FCWAY studies were performed to assess the regional binding patterns. Like [C-11]WAY, [F-18]FCWAY showed a binding pattern consistent with 5-HT-1A binding, that is, the highest binding in the frontal and medial temporal cortex, intermediate binding in other cortical regions, low binding in the thalamus and caudate nuclei, and minimal uptake in the cerebellum. By 60 to 90 min post-injection, the frontal-to-cerebellum binding ratio was difference 10:1. Preblocking studies with WAY 100635 (200 nmol/kg) administered 5 min before [F-18]FCWAY administration showed complete removal of specific binding, that is, highly uniform low binding levels in all regions. Longer lived PET radionuclides (Br-76 and I-124) are also under development, along with the technetium isotope Tc-94m. We also continue to produce At-211 for use in alpha particle therapy.